1-aceto-substituted quinolizines



nited rates 3,336,318 Patented Aug. 15, 1967 This invention relates tonovel substituted quinolizines and more particularly this inventionrelates to l-aceto substituted quinolizines of the general structures:

CHzRs wherein R is lower alkyl of 1 to 6 carbon atoms such as methyl,ethyl, propyl, isopropyl and the like; R is hydrogen, hydroxy, keto orlower acyloxy of 1 to 6 carbon atoms such as formyloxy, acetoXy,propionyloxy and the like; R is hydrogen or lower alkyl of 1 to 6 carbonatoms; R; and R are each hydrogen, hydroxy or lower acyloxy of 1 to 6carbon atoms and n is an integer of from 1 to 2. The symbols R R R R Rand n as used hereinafter have the same meaning as defined. 7

This invention also includes Within its scope a novel process for theproduction of the above compounds.

The compounds of this invention exhibit significant and interestingsteroidal-like properties. They are useful in the treatment ofcirculatory collapse, as anti-inflammatory agents and in endocrinereplacement therapy. In use these compounds are combined with an inertpharmaceutical carrier to form dosage forms such as tablets, capsules,suspension, suppositories, solutions for injection and the like with theactive ingredient being present from about 0.5 to 100 mg. per dosageunit. They may also be combined with a carrier such as petrolatum andused as a topical anti-inflammatory agent in a ratio of about 1:100.

In addition, the compounds of this invention are useful as startingmaterials for the production of other substituted quinolizines.

The compounds of this invention when n is one has the followingnumbering system:

CH R

C O I According to our novel process, these compounds may be preparedusing as starting materials, compounds of the structure IV:

CHz-Rs IV The preparation and the description of the above startingmaterials are described in our copending application Ser. No. 473,811,filed July 21, 1965. For a more detailed description as to the sourcesof our starting ma terials, see Ser. No. 323,896, now US. Patent3,261,839. The starting material IV is converted to the compounds ofthis invention by treatment with a metal-amine reducing system in thepresence of a protondonor such as an alcohol. Among metals useful forthis reduction are, for example, sodium, lithium and potassium. Usefulcommon solvents are, for example, liquid ammonia and low molecularweight amines such as methylamine, ethylamine and the like. Alcoholsuseful as proton donors in this reaction are, for example, methanol,ethanol, propanol, butanol, iso-butanol, t'butanol and the like.Employing such a reducing system as described, the starting material IVis converted to the corresponding enol ether corresponding to structureI. This reaction is usuallyv accompanied by concurrent reduction of theacetyl group at position 1, unless precautionary measures are taken toavoid this side reaction. Thus, we have found this may be accomplishedby converting the acetyl group to the corresponding cyclic-ketal,preferably its ethylene ketal corresponding to V below:

CHzRs The process may be efiected employing the usual Salmi conditionsdescribed in Ben, vol. 71, page 1803 (1938).

Alternatively, metal-amine reduction of IV without prior protection ofthe ketone may be carried out to yield an alcohol of the Formula VI:

which may then be re-oxidized to I under appropriate conditions such asunder the conditions described by Oppenauer oxidation, H. Meerwein andR. Schmidt, Ann. 444, 221 (1925).

It is apparent to those skilled in the art that the metalamine-alcoholconditions described in this invention will also bring about concurrentconversion of any ester groups at R and R to the corresponding alcoholsand these alcoholic groups may then be re-esterified by standardprocedures known to the art. Likewise, it is apparent that a keto groupat R will also be reduced to the corresponding alcohol unless protectedand that re-oxidation to the alcohol may also be eifected after themetal-amine alcohol procedure.

The compounds of this invention corresponding to structure I may then behydrolyzed under mild acidic conditions to yield the correspondingunconjugated ketone II or they may be hydrolyzed under more vigorousacidic conditions, whereby rearrangement of the double bond takes placeto yield the conjugated ketone III. Alternatively, compound 11 may beconverted to III in the presence of a base such as sodium or potassiumhydroxide.

The following examples are included in order further to illustrate theinvention. All temperatures are given in degrees centigrade. Roomtemperature is about 2 C. to 30 C.

EXAMPLE 1 ],2,3,3a,5,6,7,10,10a,11,12,12a dodecahydro 1ethylenedioxyacetyl 8 methoxy 11 hydroxy 12methyl-benz[a]cyclopentaU]quinolizinc A solution of gr. of1,2,3,3a,5,6,10b,11,12,12a-decahydro 1 acetyl 8 methoxy ll hydroxybenz[a]- cyclopenta[f]quinolizine hydrochloride and 5 gr. ofptoluenesulfonic acid in 50 ml. of ethylene glycol is diluted with 300ml. of benzene and refluxed for 4 hr. under a water separator. Thesolution is cooled, washed with 5% sodium hydroxide solution, dried overmagnesium sulfate and the benzene removed. The ketal thus obtained isdissolved in a mixture of 200 ml. of tetrahydrofuran and 50 ml. oft-butanol and added to 600 ml. of liquid ammonia. Lithium (4.5 gr.) isadded in small pieces and the mixture is stirred for 2 hr. at reflux.The blue color is discharged by the addition of ethanol. The ammonia isallowed to evaporate and the tetrahydrofuran and t-butanol are removedby distillation. The residue is partitioned between water and methylenechloride. The organic phase is dried and concentrated to give1,2,3,3a,5,6,7,10,10b,11, 12,12a dodecahydro 1 ethylendioxyacetyl 8meth- 4- oxy 11 hydroxy 12a methyl -benz[a]cyclopenta- [f]quinolizine asa white solid, M.P. 197-200 C.

EXAMPLE 2 1,2,3,3a,5,6,7,8,9,10,10b,11,12,12a tetradecahya'ro 1- acetyl11 hydroxy-IZu-methyl-benz[a]cyclopenta[f] quinolizine-8-0ne A solutionof 1.0 gr. of 1,2,3,3a,5,6,7,10,10b,11,12,12adodecahydro 1ethylendioxyacetyl 8 methoxy l1- hydroxy12a-methyl-benz[a]cyclopenta[f]quinolizine in 20 ml. of methanol istreated with 1 gr. of oxalic acid dihydrate and the solution is left atroom temperature for 4 hr. The solution is evaporated to a paste andpartitioned between ethyl acetate and 5% sodium hydroxide solution. Theorganic phase is dried and concentrated to an oil. The oil isrecrystallized from ethyl acetate to give 1,2,3,3a,5,6,7,8,9,1(),10b,11,12,12a tetradecahydro 1 acetyl 11- hydroxy 12a methylbenz[a]cyclopenta [flquinolizine- 8-one as White crystals, M.P. 178l80C.

EXAMPLE 3 1,2,3,3a,5,6,8,9,10,10a,10b,11,12,12a tetradecahydro 1- acetyl11 hydmxy-IZa-methyl-be'nz[a]cycl0penta[f] quin0lizine-8-0ne A solutionof 5 gr. of 1,2,3,3a,5,6,7,10,10b,11,12,12adodecahydro 1ethylenedioxyacetyl 8 methoxy 11- hydroxy 12amethyl-benz[a]cyclopenta[f]quinolizine is dissolved in 20 ml. ofconcentrated hydrochloric acid and left at room temperature for 48 hr.The solution is concentrated to dryness, and the residue is trituratedwith ethanol. The solid is recrystallized from methanol-ether to give1,2,3,3a,5,6,8,9,10,10a,10b,11,12,12a-tetradecahydrol-acetyl-l1-hydroxy-IZa-methyl-benzyl[a]cyclopenta[f]quinolizine-S-one-hydrochloride as white crystals M.P. 251252 C. Thefree base is obtained by neutralization and melts at 151152 C. afterrecrystallization from ethyl acetate.

EXAMPLE 4 1,2,3,3a,5,6,7,10,10b,11,12,12a dodecahydra 1B hydroxy1a-ethylenedioxyacetyl-8-meth0xy-I2a-methylbenz [a] cyclopentaU]quinolizine In the same way as described in Example 1, 5 gr. of1,2,3,3a,5,6,10b,11,12,12a decahydro lfi-hydroxy-luacetyl 8 methoxy 12amethyl benz[a]cyclopenta [f] quinolizine is converted to its ethyleneketal and subjected to Birch, (J. Chem. Soc., 1944, page 430) reductionto give 1,2,3,3a,5,6,7,l0,10b,11,12,12a-dodecahydro- 113 hydroxy 1aethylenedioxyacetyl 8 methoxy-12amethyl benz[a]cyclopenta[f]quinolizineas a white solid, M.P. 135-140 C.

EXAMPLE 5 1,2,3,3a,5,6,8,9,10,10a,10b,11 ,12,12a tetradecahydro-lhydroxy 1a acetyl 12a methyl benz [a1cyclopenta1[f] quinolizine-8-one Asolution of 4.6 gr. of 1,2,3,3a,5,6,7,10,10b,11,12,12adodecahydro 1Bhydroxy 1oz ethylenedioxyacetyl- 8-methoxy-12a-methyl-benz [a]cyclopenta [f] quinolizine in a mixture of 60 ml. of methanol and 40 ml.of 3 N hydrochloric acid is refluxed for 20 minutes. The mixture isconcentrated to a small volume and made basic with ammonium hydroxide.The precipitate is extracted with ether and the ether solution isconcentrated to 3.4 gr. of yellow solid. The solid is recrystallizedfrom isopropanol to give 1,2,3,3a,5,6,8,9,l0,10a,l0b,11,12,12atetradecahydro-lflhydroxy 1m acetyl 12a methyl benz[a]cyclopenta[f]quinolizine-8-one as crystals, M.P. 191194 C.

EXAMPLE 6 1,2,3,3a,5,6,7,10,10b,11,12,12a dodecahydro 1a hydroxy-LBethylenediovcyacetyl-8 methoxy-IZa-methylbenz [a] cyclop'enm f]quinolizine l LO/ In the same way as described in Example 1, 3.3 gr. of1,2,3,3a,5,6,10b,11,12,12a decahydro-la hydroxy-1B- acetyl-8 methoxy 12amethyl benz[a]cyclopenta[f] quinolizine is converted to its ethyleneketal and is subjected to Birch reduction to give 3.0 gr. of1,2,3,3a,5,6,7, 10,l0b,l1,12,12a dodecahydro-lot hydroxylit-ethylenedioxyacetyl 8 methoxy-12amethyl-benz[a]cyc1openta[f]quinolizine as a viscous oil.

EXAMPLE 7 1,2,3,3a,5,6,8,9,10,10a,10b,11,12,12a tetraa'ecahydrO-Iahydroxy-I B-acetyl 12a P methyl-hertz [a] cyclopentafi]quinolizine-S-one MeO In the same way as described in Example 5, 3.0 gr.of 1,2,3,3a,5,6,7,10,1 0b,11,12,12a dodecahydro Ill-hydroxy-lfiethylenedioxyacetyl 8 methoxy-lZa-methyl-benz[a]cyclopenta[f]quinolizineis hydrolyzed to give 1,2,3,3a,5,6,8,9,l0,l0a,10b,l1,12,12atetradecahydro-lahydroxy-15 acetyl-12a methyl-benz[a]cyclopenta[f]quinolizine-8-one as yellow crystals, M.P. 19'll93 C. afterrecrystallization from isopropanol (mixed M.P. with the product ofExample 5, l72174 0).

EXAMPLE 8 1,2,3,3a,5,6,7,10,10b,11,12,12a dodecahydro-1 hydroxy[ethylenedioxy]acetyl-8-meth0xy 12a methyl-benz[a] c'ycopenlaU] quinlizine In the same way as described in Example 1, a solution of 7.5 gr.of 1,2,3,3a,5,6,10b,11,12,12a decahydro-lacetoxy acetyl8-methoxy-12a-methylbenz[a]cyclopenta [fJquinolizine is converted to itsethylene ketal and subjected to Birch reduction to give 5.9 gr. of1,2,3,3a,5,6,7, lO,l0b,1l,12,l2a dodecahydro- 1hydroxy[ethylenedioxy]acetyl 8 methoxy-12a-methyl-benz[a]cyclopenta[f]quinolizine as a heavy yellow oil which solidifies to a low meltingsolid on standing.

EXAMPLE 9 1,2,3,3a,5,6,8,9,10,10a,10b,11,12,12a letradecahydro 1-acetoxyacetyl 12a methyl benz[a] cycl0penta[f] quinolizine-8-one OAC Asolution of 5.9 gr. of l, 2, 3, 3a,5,6,7,l0,10b,11,12,12adodecahydro 1hydroxy[ethylenedioxy]acetyl-S-methoxyl2a-methyl-benz[a]cyclopenta[f]quinolizine is dissolved in 50 ml. ofconcentrated hydrochloric acid and heated to for 10 min. The mixture iscooled and made basic with ammonium hydroxide. The yellow oil isextracted with methylene chloride and dissolved in a mixture of 200 ml.of acetic acid and 50 ml. of acetic anhydride. 5 gr. ofp-toluenesulfonic acid are added and the mixture is set aside overnightat 25 C. The mixture is concentrated to an oil, ice and dilute ammoniumhydroxide are added, andrthe oil is extracted with ether. The'ether isremoved and the residue is chromatographed on 500 gr. fiuorisil. Thecolumn is washed with benzene, methylenechloride and anhydrous ether.The column is then eluted with a 10% solution of ethanol in ether togive 1.2 gr. of a solid. The solid is recrystallized from isopropanol togive 1,2,3,3a,5,6,8,9,10,l0a,10b,11,12,12atetradecahydro 1acetoxyacetyl-lZa-methyl-benz[a]cyclopenta[f] quinolizine-8-one as whitecrystals, M.P. 122- 125 C.

'2 EXAMPLE 1,2,3,3a,5,6,7,l0,l0b,11,12,12a d0decahydr0-1,11dillydroxy-I-hydroxy[ethylenedioxflacetyl 12a methyl-8-methoxy-benz[a]cycl0penta[f]quinolizine MeO In the same way asdescribed in Example 1, a sOlutiOn of 1.5 gr. of1,2,3,3a,5,6,l0b,11,12,12a-decahydro-1, 11 dihydroxy 1acetoXyacetyl-8-methoxy-12a-methylbenz[a]cyclopenta[f]quinolizine isconverted to its ethylene ketal and subjected to Birch reduction to give1,2,3, 3a,5,6,7,10,l0b,11,12,12a dodecahydro1,11-dihydroxyl-hydroxy[ethylenedioxy]acetyll2a-methyl-8-n1ethoxybenz[a]cyclopenta[f]quinolizine as white crystals,M.P. 199-201" C. after recrystallization from ethanol.

EXAMPLE 11 1,2,3,3a,5,6,8,9,10,10a,10b,11,12,12a tetradecahydro 1,II-dilzydroxy 1 hydraxyacetyl 12a mcthyl-benz[a] cyclopenta [f]-quin0lizine-8-0ne 1,2,3,3a,5,6,7,10,10b,11,12,12a a'odecahydroI-hydroxy- 1 hydroxy-[ethylenedioxflacetyl 8 methoxy12amethyl-benz[a]cyclopenta- [f] quinolizine MeO In the same way asdescribed in Example 1, 7.0 gr. of 1,2,3,3a,5,6,10b,11,12,12a decahydro1 hydroxy 1- acetoxyacetyl 8 methoxy 12a methyl-benz[a]cyclopenta[f]quinolizine is converted to its ethylene ketal and subjected to Birchreduction to give 1,2,3,3a,5,6,7,10,10b, 11,12,12a dodecahydro 1 hydroxy1 hydroxy [ethylenedioxy] acetyl 8 methoxy 12a methyl-benza]cyclopenta[f]quinolizine as White crystals, MP. 201-- 204 C. afterrecrystallization from isopropanol.

In the same way as described in Example 2, 2.0 gr. of1,2,3,3a,5,6,7,10,10b,11,12,12a dodecahydro l-hydroxy- 1hydroxy[ethylenedioxy]acetyl 8 methoxy12ametl1yl-benz[a]cyclopenta[f]quinolizine is hydrolyzed to give1,2,3,3a,5,6,7,8,9,10,10b,11,12,12a-tetradecahydro-1- 1 hydroxy 1hydroxyacetyl 12a methyl-benz[a] cyclopenta[f] quinolizine 8-one aswhite crystals, M.P. 183-184 C. after recrystallization fromethylacetate.

It is understood that the foregoing detailed description is given merelyby way of illustration and that many variations may be made thereinwithout departing from the spirit of our invention.

Having described our invention, what we desire to secure by LettersPatent is:

1. Compounds of the formula:

wherein R is lower alkyl, R is hydrogen, R is hydrogen, methyl or ethyl,R is hydroxy or acyloxy of a carboxylic acid and R is hydrogen oracyloxy of a carboxylic acid and n is 1 or 2.

2. Compounds of the formula:

1 4. Compounds of the formula:

CHzRu 3)n R10 i i CHaRa CHgRu =0 I R4 R2 N/ ED-1 wherein Ri is loweralkyl, R is hydroxy, acyloxy of a carboxylic acid or keto, R ishydrogen, methyl or ethyl, R is hydrogen and R is hydrogen, hydroxy oracyloxy of a carboxylic acid and n is 1 or 2.

3. Compounds of the formula:

CHaRs CHzRs wherein R is lower alkyl, R and R are each hydrogen, l R ishydrogen, methyl or ethyl and R is hydroxy or 0 acyloxy of a carboxylicacid 'and n is 1 or 2.

4. COMPOUNDS OF THE FORMULA: